Blood Tests for Genetic Thrombophilia Workup
Order a comprehensive thrombophilia panel that includes both molecular genetic testing (Factor V Leiden and Prothrombin G20210A mutations) and functional coagulation assays (antithrombin III, protein C, and protein S), along with plasma homocysteine levels. 1
Core Genetic Tests
Molecular/DNA-Based Tests
- Factor V Leiden mutation (R506Q): This is the most common inherited thrombophilia, accounting for 90-95% of activated protein C resistance cases and should be the cornerstone of genetic testing. 1, 2
- Prothrombin G20210A mutation: This is the second most common genetic thrombophilia (present in 1-2% of the general population) and the DNA test can be multiplexed with Factor V Leiden testing for efficiency. 1, 3
Functional Coagulation Assays
- Antithrombin III functional assay: Deficiency is too genetically heterogeneous for routine molecular testing, so functional assays are the standard approach. 1
- Protein C functional assay: Like antithrombin III, protein C deficiency requires functional testing rather than molecular analysis due to genetic heterogeneity. 1
- Protein S functional assay: Similarly requires functional testing for the same reasons as protein C and antithrombin III. 1
Biochemical Testing
- Plasma homocysteine level: Hyperhomocysteinemia interacts synergistically with Factor V Leiden to increase venous thrombosis risk 20-fold, making this measurement more informative than molecular testing for MTHFR variants. 1, 3
Additional Considerations for Acquired Thrombophilias
While your question focuses on genetic predisposition, the American College of Medical Genetics recommends also testing for acquired conditions that interact with genetic factors:
- Lupus anticoagulant: Part of comprehensive risk stratification for recurrent thrombosis. 1
- Anticardiolipin antibody: Should be included in panel testing alongside hereditary factors. 1
Critical Timing Considerations
Perform testing at least 2 weeks after discontinuing anticoagulation therapy, or ideally before starting anticoagulation. 4 Functional assays for protein C, protein S, and antithrombin III can be falsely abnormal during acute thrombosis or while on anticoagulants. 5 Wait at least 3 months after an acute thrombotic event for phenotypic testing. 5
What NOT to Test
- Other Factor V mutations (Factor V-Cambridge, Factor V-Hong Kong, R2 allele): Factor V Leiden (R506Q) is currently the only molecular analysis of the factor V gene indicated in routine thrombotic risk workup. 1
- MTHFR C677T molecular testing alone: Plasma homocysteine measurement is more informative than genotyping, as the mutation accounts for only one-third of hyperhomocysteinemia cases. 1
Clinical Context Matters
The American College of Medical Genetics emphasizes that venous thrombosis is multifactorial, and identifying multiple genetic risk factors is common. 1 This panel approach allows for proper risk stratification to target anticoagulation therapy to those at highest risk, balancing the significant morbidity and mortality of recurrent thrombosis against bleeding risks. 1
Testing should be reserved for patients with documented venous thromboembolism, not for general population screening or routine pre-oral contraceptive screening. 4, 5 The highest yield is in patients under age 50 with venous thrombosis, those with thrombosis in unusual sites (hepatic, mesenteric, cerebral veins), recurrent thrombosis, strong family history, or pregnancy/oral contraceptive-associated thrombosis. 4